Autotaxin is an inflammatory mediator and therapeutic target in thyroid cancer

Abstract

Autotaxin is a secreted enzyme that converts extracellular lysophosphatidylcholine to lysophosphatidate (LPA). In cancers, LPA increases tumour growth, metastasis and chemoresistance by activating six G-protein coupled receptors. We examined O200 human thyroid biopsies. Autotaxin expression in metastatic deposits and primary carcinomas was four-to tenfold higher than in benign neoplasms or normal thyroid tissue. Autotaxin immunohistochemical staining was also increased in benign neoplasms with leukocytic infiltrations. Malignant tumours were distinguished from benign tumours by high tumour autotaxin, LPA levels and inflammatory mediators including IL1b, IL6, IL8, GMCSF, TNFa, CCL2, CXCL10 and platelet-derived growth factor (PDGF)-AA. We determined the mechanistic explanation for these results and revealed a vicious regulatory cycle in which LPA increased the secretion of 16 inflammatory modulators in papillary thyroid cancer cultures. Conversely, treating cancer cells with ten inflammatory cytokines and chemokines or PDGF-AA and PDGF-BB increased autotaxin secretion. We confirmed that this autotaxin/inflammatory cycle occurs in two SCID mouse models of papillary thyroid cancer by blocking LPA signalling using the autotaxin inhibitor ONO-8430506. This decreased the levels of 16 inflammatory mediators in the tumours and was accompanied by a 50-60% decrease in tumour volume. This resulted from a decreased mitotic index for the cancer cells and decreased levels of vascular endothelial growth factor and angiogenesis in the tumours. Our results demonstrate that the autotaxin/inflammatory cycle is a focal point for driving malignant thyroid tumour progression and possibly treatment resistance. Inhibiting autotaxin activity provides an effective and novel strategy for decreasing the inflammatory phenotype in thyroid carcinomas, which should complement other treatment modalities.

Tumor-induced inflammation in mammary adipose tissue stimulates a vicious cycle of autotaxin expression and breast cancer progression

“…Recently, we showed that high expression of ATX and inflammatory mediators distinguishes thyroid tumors from benign thyroid nodules. LPA treatment of thyroid cancer cells significantly increases the production of 16 inflammatory mediators, which in turn increase ATX production by the cancer cells (65). Thyroid tumor growth in mouse xenograft models was slowed by >50% by treatment with ONO‐8430506 (65), accompanied by a significant decrease in tumor expression of 16 inflammatory mediators (65), which in cell culture increased thyroid cancer cell growth (65).…”

Tetracyclines increase lipid phosphate phosphatase expression on plasma membranes and turnover of plasma lysophosphatidate

“…It could also have been caused secondary to the decrease in LPA concentrations because LPA can increase S1P release from cells ( 42 ). However, we think that this is unlikely because decreasing plasma LPA concentrations with an ATX inhibitor did not lower the concentration of circulating S1P ( 13 ). A further possibility is that tetracyclines exert an anti-infl ammatory effect ( 43,44 ), which might indirectly decrease plasma S1P concentrations ( 45 ).…”

Dexamethasone decreases the autotaxin‐lysophosphatidate‐inflammatory axis in adipose tissue: implications for the metabolic syndrome and breast cancer

“…This ATX-LPA-inflammatory axis in cancers promotes tumor growth, metastasis, and the loss of efficacy of chemotherapy and radiotherapy (6,12). The cycle can be attenuated in thyroid and breast cancer by inhibiting ATX, which decreases the production of .16 inflammatory cytokines and chemokines in the inflamed areas (13,14). Also, increasing the low LPP1 activity in breast and thyroid cancer cells decreases inflammation, tumor growth, and metastasis (15).…”